Details of a Researcher - Takahashi, Shinichi

Papers - Takahashi, Shinichi

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Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery

Kato C., Ueda K., Morimoto S., Takahashi S., Nakamura S., Ozawa F., Ito D., Daté Y., Okada K., Kobayashi N., Nakahara J., Okano H.

Inflammation and Regeneration 44 ( 1 ) 2024.12

Background: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. Methods: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. Results: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. Conclusions: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

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Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS)

Harada S., Iida M., Miyagawa N., Hirata A., Kuwabara K., Matsumoto M., Okamura T., Edagawa S., Kawada Y., Miyake A., Toki R., Akiyama M., Kawai A., Sugiyama D., Sato Y., Takemura R., Fukai K., Ishibashi Y., Kato S., Kurihara A., Sata M., Shibuki T., Takeuchi A., Kohsaka S., Sawano M., Shoji S., Izawa Y., Katsumata M., Oki K., Takahashi S., Takizawa T., Maruya H., Nishiwaki Y., Kawasaki R., Hirayama A., Ishikawa T., Saito R., Sato A., Soga T., Sugimoto M., Tomita M., Komaki S., Ohmomo H., Ono K., Otsuka-Yamasaki Y., Shimizu A., Sutoh Y., Hozawa A., Kinoshita K., Koshiba S., Kumada K., Ogishima S., Sakurai-Yageta M., Tamiya G., Takebayashi T.

Journal of epidemiology 34 ( 8 ) 393 - 401 2024.08

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

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Factors influencing the early neurological deterioration in intracranial branch atheromatous diseases

Deguchi I., Fujiwara S., Arai N., Nakagami T., Kimura R., Oryu K., Watanabe K., Kato Y., Hayashi T., Takahashi S., Suda S.

Neurology and Clinical Neuroscience 12 ( 4 ) 217 - 224 2024.07

Background: Intracranial branch atheromatous disease (BAD)-type cerebral infarction is often associated with a progressive worsening of neurological symptoms in the acute phase. Aim: To investigate the factors influencing the occurrence of early neurological deterioration (END) in patients with BAD. Methods: We included and evaluated 198 consecutive patients (150 patients with lenticulostriate artery [LSA-BAD] and 48 patients with paramedian pontine artery [PPA-BAD]) with onset within 24 h and with a modified Rankin scale score of ≤1 before admission for END retrospectively out of 235 patients with BAD-type cerebral infarction admitted to our hospital from January 2019 to March 2023. Results: END was observed in 26 (17%) and 15 (31%) patients with LSA-BAD and PPA-BAD, respectively. Patients in the END group with LSA-BAD had significantly higher rates of diabetes mellitus and blood glucose (BG) levels on admission and lower rates of initial clopidogrel loading therapy than those in the non-END group. Patients in the END group with PPA-BAD had significantly higher BG levels on admission than those in the non-END group. In LSA-BAD multivariate analysis, the BG level on admission and initial clopidogrel loading were identified as factors influencing END (BG level [per 10 mg/dL], odds ratio [OR] 1.084, 95% confidence interval [CI] 1.008–1.166; initial clopidogrel loading, OR 0.302, 95% CI 0.101–0.901). Conclusions: Higher BG levels at stroke onset were associated with END in patients with LSA-BAD and PPA-BAD. Additionally, initial clopidogrel loading therapy suppressed END in patients with LSA-BAD.

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Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes

Leventoux N., Morimoto S., Ishikawa M., Nakamura S., Ozawa F., Kobayashi R., Watanabe H., Supakul S., Okamoto S., Zhou Z., Kobayashi H., Kato C., Hirokawa Y., Aiba I., Takahashi S., Shibata S., Takao M., Yoshida M., Endo F., Yamanaka K., Kokubo Y., Okano H.

Acta Neuropathologica 147 ( 1 ) 2024.06

ISSN 00016322

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

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Cerebral Small Vessel Disease Burden for Bleeding Risk during Antithrombotic Therapy: Bleeding with Antithrombotic Therapy 2 Study

Tanaka K., Miwa K., Koga M., Yoshimura S., Kamiyama K., Yagita Y., Nagakane Y., Hoshino H., Terasaki T., Okada Y., Yakushiji Y., Takahashi S., Ueda T., Hasegawa Y., Shiozawa M., Sasaki M., Kudo K., Tanaka J., Nishihara M., Yamaguchi Y., Fujita K., Honda Y., Kawano H., Ide T., Yoshimoto T., Ihara M., Hirano T., Toyoda K.

Annals of Neurology 95 ( 4 ) 774 - 787 2024.04

ISSN 03645134

Objective: This study was undertaken to determine the excess risk of antithrombotic-related bleeding due to cerebral small vessel disease (SVD) burden. Methods: In this observational, prospective cohort study, patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were enrolled from 52 hospitals across Japan between 2016 and 2019. Baseline multimodal magnetic resonance imaging acquired under prespecified conditions was assessed by a central diagnostic radiology committee to calculate total SVD score. The primary outcome was major bleeding. Secondary outcomes included bleeding at each site and ischemic events. Results: Of the analyzed 5,250 patients (1,736 women; median age = 73 years, 9,933 patient-years of follow-up), antiplatelets and anticoagulants were administered at baseline in 3,948 and 1,565, respectively. Median SVD score was 2 (interquartile range = 1–3). Incidence rate of major bleeding was 0.39 (per 100 patinet-years) in score 0, 0.56 in score 1, 0.91 in score 2, 1.35 in score 3, and 2.24 in score 4 (adjusted hazard ratio [aHR] for score 4 vs 0 = 5.47, 95% confidence interval [CI] = 2.26–13.23), that of intracranial hemorrhage was 0.11, 0.33, 0.58, 0.99, and 1.06, respectively (aHR = 9.29, 95% CI = 1.99–43.35), and that of ischemic event was 1.82, 2.27, 3.04, 3.91, and 4.07, respectively (aHR = 1.76, 95% CI = 1.08–2.86). In addition, extracranial major bleeding (aHR = 3.43, 95% CI = 1.13–10.38) and gastrointestinal bleeding (aHR = 2.54, 95% CI = 1.02–6.35) significantly increased in SVD score 4 compared to score 0. Interpretation: Total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting the broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy. ANN NEUROL 2024;95:774–787.

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Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial

Houkin K., Osanai T., Uchiyama S., Minematsu K., Taguchi A., Maruichi K., Niiya Y., Asaoka K., Kuga Y., Takizawa K., Haraguchi K., Yoshimura S., Kimura K., Tokunaga K., Aoyama A., Ikawa F., Inenaga C., Abe T., Tominaga A., Takahashi S., Kudo K., Fujimura M., Sugiyama T., Ito M., Kawabori M., Hess D.C., Savitz S.I., Hirano T.

JAMA Neurology 81 ( 2 ) 154 - 162 2024.02

ISSN 21686149

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P =.90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

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Recurrent Stroke with Rapid Development of Intracranial Artery Stenosis and Subsequent Successful Mechanical Thrombectomy in Essential Thrombocythemia

Kato Y., Iijima S., Kohyama S., Maeda T., Sato T., Takahashi S., Suda S.

Internal Medicine 63 ( 6 ) 847 - 852 2024

ISSN 09182918

Essential thrombocythemia is a myeloproliferative neoplasm. Ischemic stroke is frequently the first manifestation of essential thrombocythemia. We herein report a patient with JAK2V617 mutation-positive essential thrombocythemia who developed recurrent ischemic stroke with rapid development of intracranial artery stenosis and subsequently underwent successful mechanical thrombectomy. The high JAK2V617F allele burden in our patient (58.4%) may have affected the patient's condition. We discuss similar reports in the literature and the possible pathophysiologic mechanism of large artery involvement in these patients.

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Factors affecting early neurological deterioration after intravenous alteplase treatment for branch atheromatous disease

Mizuno S., Deguchi I., Takahashi S., Arai N., Nakagami T., Kimura R., Oryu K., Watanabe K., Ueda S., Fujiwara S., Kato Y., Hayashi T., Suda S.

Neurology and Clinical Neuroscience 2024

Background: Intravenous alteplase treatment is effective for acute cerebral infarction, irrespective of the stroke type. However, its value for branch atheromatous disease (BAD) remains unclear, and early neurological deterioration (END) can occur. Aim: To investigate factors affecting END after intravenous alteplase treatment in patients with acute BAD. Methods: This study included 40 consecutive patients diagnosed with cerebral infarction due to BAD in the lenticulostriate artery territory and treated with intravenous alteplase between April 2007 and March 2023. END was defined as an increase of ≥2 points in the total National Institutes of Health Stroke Scale score or ≥1 point in the motor items within 24 h post-alteplase administration compared to the score at admission. Factors affecting END were retrospectively evaluated. Results: END was observed in 17 of the 40 patients (43%). The median time from the start of alteplase administration to the worsening of neurologic symptoms was 5 h. After intravenous alteplase treatment, the END group had a significantly lower 24-h average systolic blood pressure (SBP, mean ± standard deviation mmHg) than the non-END group (142.0 ± 15.2 vs. 149.4 ± 12.0, p < 0.001). The SBP at each time point (immediately before alteplase administration and every 2 h up to 24 h after alteplase administration) was significantly lower in the END than in the non-END group at 2, 4, and 6 h after alteplase administration. Conclusions: When intravenous alteplase was administered for BAD, BP control after alteplase administration affected END. When alteplase is administered for BAD, it is important to control the blood pressure to maintain hemodynamics.

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Association between Mobility of Residual Left Atrial Thrombus and Stroke Severity in Patients with Nonvalvular Atrial Fibrillation

Kato Y., Hayashi T., Nakano S., Arai T., Fujiwara S., Watanabe K., Oryu K., Kimura R., Arai N., Nakagami T., Deguchi I., Takahashi S., Suda S.

Journal of Nippon Medical School 91 ( 3 ) 322 - 327 2024

ISSN 13454676

Background: The differences in the characteristics of ischemic stroke associated with a mobile versus nonmobile residual left atrial thrombus (LAT) are unclear. We investigated whether the mobility of an LAT detected by transthoracic echocardiography is associated with the clinical features of stroke. Methods: This study included 20 consecutive patients with nonvalvular atrial fibrillation who were ad-mitted to our hospital for treatment of acute ischemic stroke and then found to have an LAT on transthoracic echocardiography. The patients were divided into two groups: those with a mobile LAT (Group M) and those with a nonmobile LAT (Group N). The clinical, neuroradiological, and echocar-diographic variables were assessed. Results: The LAT was mobile in 11 patients (Group M) and nonmobile in nine patients (Group N). The median National Institutes of Health Stroke Scale score on admission was higher in Group M than N (17 vs. 7, respectively; p=0.196). Four patients in Group M and one in Group N developed in-hospital stroke recurrence (36% vs. 11%, respectively; p=0.319). The prevalence of large vessel occlusion (15 events in Group M and 10 events in Group N, including in-hospital recurrent events) was significantly higher in Group M than N (73% vs. 30%, respectively; p=0.049), which seemed to lead to poorer functional outcomes in Group M than N (ratio of modified Rankin scale score of 0-2 at discharge: 18% vs. 44%, respectively; p=0.336). Conclusions: The mobility of LAT may affect stroke severity in patients with nonvalvular atrial fibrillation.

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Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

Okano H., Morimoto S., Kato C., Nakahara J., Takahashi S.

Journal of Neurochemistry 167 ( 5 ) 603 - 614 2023.12

ISSN 00223042

It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.

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Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery

Morimoto S., Takahashi S., Ito D., Daté Y., Okada K., Kato C., Nakamura S., Ozawa F., Chyi C.M., Nishiyama A., Suzuki N., Fujimori K., Kondo T., Takao M., Hirai M., Kabe Y., Suematsu M., Jinzaki M., Aoki M., Fujiki Y., Sato Y., Suzuki N., Nakahara J., Okano H.

Cell Stem Cell 30 ( 6 ) 766 - 780.e9 2023.06

ISSN 19345909

iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.

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Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis

Ito D., Morimoto S., Takahashi S., Okada K., Nakahara J., Okano H.

Brain 146 ( 1 ) 13 - 19 2023.01

ISSN 00068950

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.

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Pathophysiology and Optimal Treatment of Intracranial Branch Atheromatous Disease

Deguchi I., Takahashi S.

Journal of Atherosclerosis and Thrombosis 30 ( 7 ) 701 - 709 2023

ISSN 13403478

Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700–800 μm) near the orifice of a parent artery due to atherosclerotic plaque-based thrombus (microatheroma). BAD is refractory to treatment and follows a course of progressive exacerbation, especially motor paralysis. Uniform treatment for common atherothrombotic cerebral infarction or lacunar infarction does not prevent the progressive exacerbation of BAD, and consequently affects functional prognosis. To date, various combinations of treatments have been investigated and proposed to attenuate the worsening symptoms of BAD. However, no therapy with established efficacy is yet available for BAD. Since it is the most difficult condition to treat in the area of cerebral infarction, the establishment of optimal treatment methods for BAD is keenly awaited. This review presents an overview of the acute treatments available for BAD and discusses the prospects for optimal treatment.

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Efficacy of Treatment with and without Initial Clopidogrel Loading in Branch Atheromatous Disease

Deguchi I., Osada T., Takahashi S.

Internal Medicine 62 ( 20 ) 2959 - 2964 2023

ISSN 09182918

Objective Despite aggressive therapeutic interventions during the acute phase of branch atheromatous disease (BAD)-type cerebral infarction, many patients, even those with a mild condition at the onset, experience neurological deterioration after hospitalization and develop serious deficits. We compared the therapeutic efficacy of multiple antithrombotic therapies for BAD between patients who received a clopidogrel loading dose (loading group; LG) and those without loading (non-loading group; NLG). Patients Between January 2019 and May 2022, patients with BAD-type cerebral infarction in the lenticulostriate artery admitted within 24 h of the onset were recruited. This study included 95 consecutive patients who received combination argatroban and dual antiplatelet therapy (aspirin and clopidogrel). Methods Patients were classified into the LG and NLG according to whether or not a loading dose of clopidogrel (300 mg) had been administered on admission. Changes in neurological severity [National Institutes of Health Stroke Scale (NIHSS) score] during the acute phase were retrospectively evaluated. Results There were 34 (36%) and 61 (64%) patients in the LG and NLG, respectively. On admission, the median NIHSS score was similar between the groups [LG: 2.5 (2-4) vs. NLG: 3 (2-4), p=0.771]. At 48 h following admission, the median NIHSS scores were 1 (0.25-4), and 2 (1-5) in the LG and NLG, respectively (p=0.045). Early neurological deterioration (END; defined as worsening of the NIHSS score by !4 points at 48 h after admission) occurred in 3% of LG and 20% of NLG patients (p=0.028). Conclusion Administration of a clopidogrel loading dose with combination antithrombotic therapy for BAD reduced END.

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Aseptic Meningitis after BNT-162b2 COVID-19 Vaccination: Case Report and Literature Review

Kato Y., Osada T., Araki N., Takahashi S.

Keio Journal of Medicine 72 ( 4 ) 102 - 105 2023

ISSN 00229717

We encountered a-27-year-old female patient who developed refractory severe headache and photo-phobia after the first dose of COVID-19 vaccine. Despite her prior history of migraine, we diagnosed COVID-19 vaccine-induced aseptic meningitis. Symptoms were significantly resolved after methylpred-nisolone therapy. On reviewing the literature, we could find only nine similar cases, with over half of them affecting women aged 20–40 years. Although uncommon, aseptic meningitis should be suspect-ed in patients with persistent or delayed onset of headache following COVID-19 vaccination.

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Status of neurological deficits after mechanical thrombectomy in elderly patients with ischemia

Deguchi I., Osada T., Kohyama S., Takahashi S.

Journal of Clinical Neuroscience 105 16 - 21 2022.11

ISSN 09675868

Background: Numerous studies report poorer outcomes after mechanical thrombectomy (MT) in elderly patients than in non-elderly patients. We aimed to investigate the changes in neurological symptoms after MT in elderly patients. Methods: We included 151 patients with acute stroke who independently performed activities of daily living before admission, underwent MT at our hospital between January 1, 2019 and December 31, 2021, and had successful recanalization (thrombolysis in cerebral infarction grade >2b). The subjects were divided into two groups according to whether they were aged ≥80 years (elderly group) or <80 years (non-elderly group), and the National Institutes of Health Stroke Scale (NIHSS) scores and deep and subcortical white matter hyperintensity (DSWMH) grades were compared between both groups. Results: There were 57 (38 %) and 94 (62 %) patients in the elderly and non-elderly groups, respectively. After propensity score matching, the median (interquartile range) NIHSS scores were significantly higher in the elderly group than in the non-elderly group at both 24 h (12 [5.5–19] vs 8; [2–14] P = 0.040) and 1 week (8 [3–12] vs 2.5 [0–13.5]; P = 0.041) after MT but not before MT (18 [13.5–22.5] vs 20 [14.5–24]; P = 0.549). DSWMH grades were significantly higher in the elderly group than in the non-elderly group (2 [1–3] vs 1 [0–2]; P = 0.018). Conclusions: MT in the elderly group was associated with poorer improvement in neurological symptoms from the early period after MT than in the non-elderly group, even when successful recanalization was achieved. White matter lesions may contribute to the poor neurological improvement after recanalization in the elderly group.

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Differences in oral anticoagulant prescriptions between specialists and non-specialists in patients with cardioembolic stroke caused by non-valvular atrial fibrillation

Deguchi I., Osada T., Arai N., Takahashi S.

Heart and Vessels 37 ( 5 ) 867 - 874 2022.05

ISSN 09108327

Atrial fibrillation (AF) is a common disease encountered in daily practice; however, few patients with AF received oral anticoagulant (OAC) therapy. This study focused on differences in OAC prescriptions and influencing factors between specialists (neurological and cardiovascular) and non-specialists. A retrospective comparative analysis was conducted on 480 patients with acute cardioembolic stroke caused by non-valvular AF who were admitted to our hospital between January 1, 2015, and December 31, 2020. All patients had visited our hospital or other hospitals for their underlying diseases. Overall, 232 (specialist group SG) and 248 patients (non-specialist group NSG) were examined by specialists and non-specialists, respectively. The NSG had a significantly lower percentage of OAC prescriptions on admission than the SG (P < 0.01), even after propensity score matching. Factors influencing OAC prescription in the SG were age, hypertension, paroxysmal AF, dementia, CHADS2 score, and antiplatelet drug use, while those in the NSG were a history of cerebral infarction, paroxysmal AF, dementia, and antiplatelet drug use [SG: age, odds ratio (OR) 0.919, 95% confidence interval (CI) 0.865–0.976; hypertension, OR 0.266, 95% CI 0.099–0.713; paroxysmal AF, OR 0.189, 95% CI 0.055–0.658; dementia, OR 0.253, 95% CI 0.085–0.758; CHADS2 score, OR 2.833, 95% CI 1.682–4.942; and antiplatelet drug use, OR 0.072, 95% CI 0.025–0.206; NSG: cerebral infarction, OR 5.940, 95% CI 1.581–22.309; paroxysmal AF, OR 0.077, 95% CI 0.010–0.623; dementia, OR 0.077, 95% CI 0.014–0.438; and antiplatelet drug use, OR 0.024, 95% CI 0.004–0.152]. In conclusion, the OAC prescription rate was higher in patients with non-valvular AF whose family physicians were specialists at the time of cerebral infarction onset. In addition, in the SG, advanced age and hypertension were associated with not prescribing OAC, whereas a higher CHADS2 score was associated with the prescription of OACs. In the NSG, a history of cerebral infarction was associated with the prescription of OACs. Further, paroxysmal AF, antiplatelet drug use, and dementia were associated with non-OAC therapy in both the groups.

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Influence of a clinical trial in the decision-making processes of patients with amyotrophic lateral sclerosis

Kato C., Morimoto S., Takahashi S., Daté Y., Okada K., Okano H., Nakahara J., Ito D.

Journal of Neurology 269 ( 5 ) 2634 - 2640 2022.05

ISSN 03405354

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease, and patients diagnosed with ALS have a survival time of 2–5 years without life-sustaining therapy. Decision-making processes for the acceptance or decline of percutaneous endoscopic gastrostomy (PEG) and tracheostomy with invasive ventilation (TIV) therapy are complex and multifaceted. In this study, we examined whether participation or no participation in clinical trials of ALS had an influence on the decision-making processes of ALS patients. Methods: Fifty-seven consecutive ALS participants were recruited. Two participants did not wish to participate in any clinical trials, and Twenty-two participants were enrolled in clinical trials. Twenty-three participants wished to participate but could not be enrolled in any of the clinical trials because they exceeded the number of participants in these trials or they met the exclusion criteria. Result: At baseline, there was no significant difference in the preference rates for PEG and TIV between the participant and non-participant groups, but after the double-blind period/6 months, both preference rates were significantly higher in the non-participant group than in the participant group. Notably, the rate of preferred TIV in the participant group drastically decreased after the double-blind period. A single regression analysis revealed that participation in clinical trials had a strong influence on the change of TIV preference for 6 months. Conclusion: Participation in a clinical trial decreases the willingness to prolong life after the clinical trial. The present results are meaningful when designing clinical trials and discussing life-sustaining treatments with ALS patients.

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Association Between Oral Anticoagulants and Stroke Severity at Onset in Elderly Patients with Cardioembolic Stroke Due to Non-Valvular Atrial Fibrillation

Deguchi I., Osada T., Takahashi S.

Journal of Stroke and Cerebrovascular Diseases 31 ( 3 ) 2022.03

ISSN 10523057

Objectives: This study aimed to determine whether oral anticoagulant therapy affects the severity of cerebral infarction at onset in elderly patients with non-valvular atrial fibrillation. Materials and Methods: This retrospective study included 330 elderly patients (aged ≥75 years) who were hospitalized for cardioembolic stroke due to non-valvular atrial fibrillation. Patients’ medical history, stroke severity at onset (National Institutes of Health Stroke Scale score), and the prevalence of large vessel occlusion were compared between patients who received oral anticoagulant therapy (n = 109) and those who did not receive oral anticoagulant therapy (n = 221). Results: Stroke severity was significantly lower in patients who received anticoagulants than in those who did not receive anticoagulants (6 versus 12; P = 0.021). Patients who did not receive anticoagulants had a significantly higher prevalence of large vessel occlusion (52% versus 37%; P = 0.010). After resampling based on propensity score matching, both median stroke severity (7 versus 12; P = 0.046) and large vessel occlusion prevalence (36% versus 57%; P = 0.019) were significantly lower in patients who received anticoagulant therapy. Conclusions: The results of this study suggest that elderly patients with non-valvular atrial fibrillation who are administered oral anticoagulant therapy before the onset of cerebral infarction develop less severe stroke than those who are not receiving oral anticoagulant therapy. Thus, oral anticoagulant therapy should be actively considered in patients with non-valvular atrial fibrillation as it does not only prevents cerebral embolism, but also reduces the risk of severe sequelae.

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Thrombectomy for acute large vessel occlusion in posterior and anterior circulation: a single institutional retrospective observational study

Kuribara T., Iihoshi S., Tsukagoshi E., Teranishi A., Kinoshita Y., Sugasawa S., Kohyama S., Takahashi S., Kurita H.

Neuroradiology 64 ( 3 ) 565 - 574 2022.03

ISSN 00283940

Purpose: Thrombectomy has been the gold standard therapy for anterior circulation occlusion; however, studies regarding thrombectomy in posterior circulation are lacking. In this study, we compared the efficiency of thrombectomy for acute large vessel occlusion between the posterior and anterior circulation at a single institution. Methods: We retrospectively analyzed consecutive patients who underwent thrombectomy for acute large vessel occlusion at our institution between August 2014 and April 2021. Differences in the clinical background, time course, and treatment technique and outcomes were evaluated between anterior and posterior circulation occlusions. Results: Overall, 353 patients (225 men and 128 women) were included: 314 patients had anterior circulation occlusion and 39 patients had posterior circulation occlusion. Between the patients with anterior and posterior circulation occlusions, the National Institutes of Health Stroke Scale (NIHSS) score (16 [12–21] vs. 29 [19–34], respectively, p < 0.001), door-to-puncture time (65 [45–99] vs. 99 [51–121] min, respectively, p = 0.018), and mortality (22 [7%] vs. 8 [20.5%] patients, respectively, p = 0.010) were significantly different; however, favorable outcome was not significantly different. Conclusion: Higher NIHSS score, delayed treatment, and higher mortality were observed in posterior circulation occlusion than in anterior circulation occlusion; successful reperfusion and favorable outcomes were similar between them. Similar favorable outcomes and reperfusion ratio to the anterior circulation might be achieved also in the posterior circulation; however, delayed treatment and the optimal first-pass strategy might need further improvement.

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